Samatasvir (IDX719), a Potent Pan-Genotypic NS5A Inhibitor, for the Treatment of Hepatitis C Virus (HCV) Infection

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1 Samatasvir (IDX719), a Potent Pan-Genotypic NS5A Inhibitor, for the Treatment of Hepatitis C Virus (HCV) Infection Douglas Mayers, MD December 11,

2 Idenix: Advancing All-Oral, Pan-Genotypic Combination HCV Regimens Samatasvir (IDX719) phase II NS5A inhibitor - Favorable safety and potent pan-genotypic activity of samatasvir demonstrated in HCVinfected patients - Ongoing all-oral phase II 2-DAA HELIX-1 trial in combination with Janssen s simeprevir - Ongoing all-oral phase II 3-DAA HELIX-2 trial with Janssen s simeprevir and ritonavirboosted non-nucleoside inhibitor (TMC647055) - All-oral phase II combination study of samatasvir and nucleotide in 2014 IDX21437 phase I/II nucleotide prodrug inhibitor candidate - Single-dose escalation in Healthy Volunteers and HCV-infected subjects is ongoing Multiple, earlier-stage nucleotide prodrug candidates 2 Building a Leading Antiviral Franchise

3 Samatasvir: Best-in-Class Profile Among HCV NS5A Inhibitors Strong preclinical profile Granted FDA fast track designation 3-Day proof-of-concept phase I/II clinical trial in 64 GT1-4 HCVinfected patients demonstrated safety and pan-genotypic activity Two 12-week phase II all-oral DAA combination HELIX clinical trials in collaboration with Janssen Pharmaceuticals, Inc. 3 Building a Leading Antiviral Franchise

4 Samatasvir: NS5A Inhibitor Promising Profile for Combination Therapy Clean preclinical safety profile Potential for low mg doses and QD dosing in humans No in vitro interaction with 7 human CYP 450 enzymes at 10 µm (well above physiologic concentrations) No significant interaction with human transporters at physiologic concentrations Additive antiviral effects with other HCV DAAs No in vitro DDIs with common HBV and HIV therapeutic agents 4 Building a Leading Antiviral Franchise

5 Samatasvir Strong Preclinical Profile EC 50 vs HCV replicon (pm) a 1b 2a 2a (virus) 3a 4a 5a Samatasvir Daclatasvir Potent activity against genotypes 1a, 1b, 2a, 3a, 4a and 5a with high selectivity indices in vitro pm activity overall 5 Building a Leading Antiviral Franchise

6 Samatasvir Phase I/II Clinical Trial Potent and Pan-genotypic in 3-Day Proof-of-Concept Study Three-day proof-of-concept clinical trial in 64 HCV-infected patients - GT 1 patients: placebo, 25 mg QD, 50 mg QD, 50 mg BID or 100 mg QD - GT 2, 3 or 4 patients: placebo, 50 mg BID or 100 mg QD Well-tolerated with no treatment-emergent serious adverse events reported and no safety-related discontinuations Potent antiviral activity across genotypes GT1-4 in HCV-infected patients with mean maximal viral load reductions up to ~4.0 log 10 IU/mL Dose Mean Maximum Viral Load Reduction GT1a n=23 GT1b n=5 GT2 n=8 GT3 n=8 GT4 n=8 25 mg QD 3.3 log log mg QD 3.6 log log mg BID 3.2 log log log log mg QD 3.5 log log log log 10 6 Building a Leading Antiviral Franchise

7 Samatasvir Phase I/II Clinical Trial 3-Day Proof-of-Concept Antiviral Activity in GT 1-4 HCV-Infected Patients 7 Building a Leading Antiviral Franchise

8 Samatasvir Phase I/II Clinical Trial 3-Day Proof-of-Concept Antiviral Activity in GT 2 HCV-Infected Patients Individual antiviral activity in genotype 2 HCV-infected subjects M31 NS5A Polymorphism was associated with reduced antiviral responses in GT 2 but not GT 4-infected subjects 8 Building a Leading Antiviral Franchise

9 HELIX-1 Clinical Trial Design All-oral 12-week 2-DAA Combination Regimen n=~20 Treatment naïve, GT 1b 50 mg samatasvir mg simeprevir + RBV Part A n=~20 n=~20 Treatment naïve, GT 1b 100 mg samatasvir mg simeprevir + RBV Treatment naïve, GT 1b 150 mg samatasvir mg simeprevir + RBV Study weeks Week 12 (EOT) Week 16 (SVR4) Week 24 (SVR 12) Week 36 (SVR 24) Part B is currently enrolling exploratory arms designed to evaluate safety and antiviral activity of simeprevir and ribavirin combined with: - 25 mg dose of samatasvir in GT 1b-infected patients mg dose of samatasvir in GT 6-infected patients mg dose of samatasvir in additional GT 1b-infected patients Objectives: safety and tolerability, efficacy (primary SVR 4 with supportive SVR 12 and SVR 24 ), pharmacokinetics and pharmacodynamics, emergence of resistance 9 Building a Leading Antiviral Franchise

10 HELIX-2 Clinical Trial Design All-oral 12-week 3-DAA Combination Regimen n=~20 Treatment naïve or relaspers, GT 1 50 mg samatasvir + 75 mg simeprevir mg TMC647055/r + RBV n=~20 Treatment naïve or relapsers, GT 1 50 mg samatasvir + 75 mg simeprevir mg TMC647055/r Study weeks Week 12 (EOT) Week 16 (SVR4) Week 24 (SVR 12) Week 36 (SVR 24) Additional exploratory arms may be added to evaluate safety and antiviral activity Objectives: safety and tolerability, efficacy (primary SVR 4 with supportive SVR 12 and SVR 24 ), pharmacokinetics and pharmacodynamics, emergence of resistance 10 Building a Leading Antiviral Franchise

11 Novel Nucleotide Prodrug Discovery Program Identify promising compounds in vitro and in mouse and monkey - Triphosphate production, kinetics of metabolism, favorable safety, cytotoxicity - Levels of TP in the liver after oral administration in vivo Explored diverse spectrum of nucleotides - Purines and pyrimidines, known and novel prodrugs, and 2 Me sugars and some novel sugars Strong intellectual property position - Covering diverse range of candidate compounds in R&D pipeline NUC discovery capability also can be applied to non-hcv therapeutic areas - External interest in screening library - Restructured Novartis agreement allows flexibility to explore other indications 11 Building a Leading Antiviral Franchise

12 IDX21437: Next-Generation Uridine Nucleotide Prodrug Phase I/II clinical trial ongoing Single-dose escalation in Healthy Volunteers and HCV-infected subjects ongoing Potent, pan-genotypic activity in vitro; high liver triphosphate levels generated in vivo Potential for high potency at low once-daily doses in the clinic Suitable for fixed-dose combination with samatasvir and other DAAs Favorable preclinical safety profile Preclinical toxicology profile to date provides good safety margins for anticipated clinical doses Clean genotoxicity and cardiac safety assessments to date 12 Building a Leading Antiviral Franchise

13 IDX21437: Phase I/II Clinical Trial Design A phase I/II study assessing single and multiple doses of IDX21437 in healthy volunteers and HCV-infected patients Single Dose Healthy Volunteers IDX21437 monotherapy Treatment naïve, GT 1 IDX21437 monotherapy Treatment naïve, GT 1, Cirrhotic IDX21437 monotherapy (1 dose) Healthy Volunteers IDX21437 monotherapy (1 dose) Multiple Dose (7-day) Treatment naïve, GT 1 IDX21437 monotherapy Treatment naïve, GT 2-6 IDX21437 monotherapy Treatment naïve, GT 1, Cirrhotic IDX21437 monotherapy (1 dose) 13 Building a Leading Antiviral Franchise

14 Summary/Conclusions Samatasvir has been safe and well tolerated after single and multiple doses of up to 150 mg in healthy volunteers up to 14 days duration, and in HCV-infected patients up to 12 weeks duration Samatasvir proof-of-concept study in HCV GT 1 4-infected patients showed potent, pan-genotypic activity with mean maximal viral load reductions up to approximately 4.0 log 10 IU/mL In vitro results for samatasvir were predictive of in vivo antiviral activity All-oral 12-week phase II combination studies including samatasvir in collaboration with Janssen ongoing Initiation of 12-week combination studies of samatasvir and IDX21437 planned in Building a Leading Antiviral Franchise

15 Acknowledgments Idenix Montpellier Medicinal Chemistry team Clinical team Idenix Cambridge Clinical team Biology team DMPK team CMC team With special thanks to all of our investigators and patients who participated in our clinical trials of samatasvir 15 Building a Leading Antiviral Franchise